Solution to the C₃–Arylation of Indazoles: Development of a Scalable Method

3-(Hetero)­arylindazoles are important motifs in several biologically active compounds. Mild and flexible palladium-mediated Negishi reaction conditions are reported for the introduction of (hetero)­aryl moieties at the 3-position of <i>N</i>(2)-SEM-protected indazoles in high yields. The requisite Zn-species are readily obtained via regioselective deprotonation and subsequent transmetalation. The methodology tolerates a variety of functional groups on both coupling partners and has been extended to bis-haloarene and heteroarene coupling partners where the most reactive halogen reacts first, leaving the second halogen for subsequent functionalization

Discovery of a 3‑(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity

Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson’s disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (<b>1</b>): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2